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Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial
Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, et al
Jama. 2021
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Editor's Choice
Abstract
IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02735707.
PICO Summary
Population
Critically ill patients with COVID-19 from 129 sites in 4 countries, enrolled in the ongoing REMAP-CAP trial (n= 2,011).
Intervention
2 units of high-titre, ABO-compatible convalescent plasma (n= 1,084).
Comparison
No convalescent plasma (n= 916).
Outcome
The median number of organ support-free days was 0 in the convalescent plasma group and 3 in the no convalescent plasma group. The in-hospital mortality rate was 37.3% for the convalescent plasma group and 38.4% for the no convalescent plasma group and the median number of days alive and free of organ support was 14 and 14, respectively. Serious adverse events were reported in 3% of participants in the convalescent plasma group and in 1.3% of participants in the no convalescent plasma group.
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Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial
Bégin P, Callum J, Jamula E, Cook R, Heddle NM, Tinmouth A, Zeller MP, Beaudoin-Bussières G, Amorim L, Bazin R, et al
Nature Medicine. 2021
Abstract
The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset ( NCT04348656 ). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm-relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94-1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02-1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57-0.95 and OR = 0.66, 95% CI 0.50-0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14-2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
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Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, Berger JS, Gong, MN, Carrier M, Reynolds HR, Kumar A, Turgeon AF, et al
The New England Journal of Medicine. 2021
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Editor's Choice
Abstract
BACKGROUND Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).
PICO Summary
Population
Critically ill patients with severe COVID-19 (n= 1,098).
Intervention
Therapeutic-dose anticoagulation with heparin (n= 534).
Comparison
Usual-care pharmacologic thromboprophylaxis (n= 564).
Outcome
The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis. The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis.
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Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial
Houston BL, Lawler PR, Goligher EC, Farkouh ME, Bradbury C, Carrier M, Dzavik V, Fergusson DA, Fowler RA, Galanaud JP, et al
Clinical Trials (London, England). 2020;:1740774520943846
Abstract
BACKGROUND Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.
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A Scoping Review of Registered Clinical Trials of Convalescent Plasma for COVID-19 and a Framework for Accelerated Synthesis of Trial Evidence (FAST Evidence)
Zheng K, Liao G, Lalu MM, Tinmouth A, Fergusson DA, Allan DS
Transfusion Medicine Reviews. 2020
Abstract
Many parallel studies of convalescent plasma with modest enrolment projections have been launched for the treatment of COVID-19. By pooling data from multiple parallel studies that are similar, we can increase the effective sample size and achieve enough statistical power to determine effectiveness more quickly through meta-analysis. A scoping review of registered clinical trials of convalescent plasma for COVID-19 was conducted to assess the feasibility of performing a rapid and timely meta-analysis that will support accelerated review for approval and implementation. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched April 23, 2020. Trials were included if they utilized convalescent plasma to treat or prevent COVID-19. Forty-eight registered trials (projected to enroll more than 5000 subjects) of convalescent plasma were identified and included for analysis. The majority of studies (33 studies with 4440 projected enrolment) will address the treatment of severe and/or critical cases of COVID-19. Twenty-nine studies are controlled and 17 of these are reported as actively recruiting. The combined enrolment of patients from similar studies should be sufficient to determine meaningful improvements in mortality, rates of admission to intensive care and need for mechanical ventilation by the end of 2020-sooner than any individual study could determine effectiveness. Accessing supplemental outcome data from investigators may be needed; however, to align reporting of some outcomes from these studies. Heterogeneity in product potency due to different antibody titers is anticipated and studies using conventional treatment as controls instead of placebo may complicate our understanding of efficacy. Convalescent plasma is being tested in ongoing controlled studies, largely to treat severe and/or critical cases of COVID-19. Sufficient combined power to detect clinically important reductions in multiple outcomes, including mortality, is expected by September 2020. Regulatory approval, funding and implementation by blood operators could be accelerated by planned meta-analysis as study results become available.